Process for the preparation of aryl-pyridinyl compounds

ABSTRACT

A process is described for the preparation of arylpyridine compounds by aryl-aryl cross-coupling reactions between a halopyridine and an arylmagnesium halide carried out in the presence of a catalytic amount of a zinc salt and a catalytic amount of palladium. The zinc salt is preferably selected from ZnCl 2 , ZnBr 2  and/or Zn(OAc) 2 , while the palladium is preferably used in the form of Pd(PPh 3 ) 4  or Pd(OAc) 2  +4 PPh 3 . The reaction can also be carried out in the presence of bidentate phosphines, such as, for example, 1,3-bis(diphenylphosphine)propane or 1,4-bis(diphenylphosphine)-butane. It is thus possible to obtain molar yields higher than 97% (calculated relative to the halopyridine) and a catalyticity of more than 2000.

Arylpyridines are generally used in organic synthesis as intermediatesfor the preparation of various kinds of compound; of these,4-(2′-pyridyl)benzaldehyde is a useful intermediate in the preparationof antiviral drugs and, in particular, of HIV protease inhibitors, suchas, for example, the azahexane heterocyclic derivatives described ininternational patent application WO 97/40029, which is incorporatedherein by reference; among the antiviral drugs concerned, one ofparticular interest is, for example, that indicated by the abbreviationBMS-232632 in Drugs of the Future 1999, 24(4):375, the structuralformula of which is given below:

Arylpyridines can be prepared by aryl-aryl cross-coupling reactions(Lohse et al.; Synlett. 1999, Vol. 1; 45-48. Minato et al., TetrahedronLetters, Vol. 22, no. 52, pp. 5319-5322. 1981. Ei-ichi Negishi et al.Heterocycles 1982, Vol. 18; 117-122), or coupling reactions between twoaryl compounds in accordance with the scheme given below:

ArMeX+PyY→ArPy+MeXY

wherein:

Ar represents an aryl compound and Py represents a pyridine compound; Merepresents a metal selected from Mg, Zn and Sn, and X represents Br, Cl,I; or, alternatively, Me and X, together, represent B(OH)₂ or BR₂(wherein R is an alkyl group); Y represents Br, Cl or I.

In particular, 4-(2′-pyridyl)benzaldehyde is normally prepared startingfrom 4-bromobenzaldehyde and 2-bromopyridine (Bold et al.; J.Med.Chem.1998, 41, 3387 and WO 97/40029), according to the scheme given in FIG.1.

The method provides for the conversion of 4-bromobenzaldehyde into thecorresponding acetal and then into the Grignard reagent BrMgC₆H₄CH(OR)₂(compound 1). The Grignard reagent is then reacted with 2-bromopyridine(compound 2) in the presence of NiCl₂ and1,3-bis(diphenylphosphine)propane (Inorg. Chem. 1966, 1968) to give,after the conversion of the acetal group into an aldehyde group, bytreatment in an acidic aqueous medium, 4-(2′-pyridyl)benzaldehyde(compound 3).

However, that method has disadvantages of not inconsiderable importance,such as the use of a toxic and carcinogenic catalyst such as the nickelsalt and, above all, poor reproducibility, which is all the greater thesmaller the amount of catalyst employed.

The object of the work which resulted in the present invention wastherefore to find a novel and reliable aryl-aryl cross-coupling processbased on the use of metals that are both other than nickel and capableof leading to the formation of arylpyridines, and in particular4-(2′-pyridyl)benzaldehyde, with reproducible and industriallysatisfactory yields, even in the presence of very small amounts ofcatalyst.

It has now been found that a zinc salt can be used in a catalytic amountand in combination with palladium to catalyse efficiently the formationof arylpyridines by aryl-aryl cross-coupling reactions. In particular,as will be seen hereinafter, it has been found that the zinc salt incombination with palladium catalyses with optimum yields, a high levelof productivity and, above all, with a high degree of catalyticity thereactions for the synthesis of arylpyridines according to the generalscheme given below

wherein A and B, which are the same or different from one another,represent H; a linear or branched C₁-C₈ alkyl; an optionally substitutedacetal group; an aryl or a benzyl, which are optionally substituted bygroups that do not interfere with a Grignard reaction; and X₁ and X₂,which are the same or different from one another, represent Cl, Br or I.

The subject-matter of the present invention is particularly interestingbearing in mind that coupling reactions catalysed by palladium andmediated by zinc salts have already been described in Jetter et al.,SYNTHESIS, June 1998, 829-831. However, in that article the zinc saltwas used in amounts of approximately 2 equivalents with final yields of70-80%; by increasing the concentration of the zinc salt to 3equivalents it was possible to obtain a substantial increase in theyield which, however, fell by 40% when only one equivalent of the zincsalt was used.

With the present invention, it has, however, surprisingly been foundthat the use of a catalytic amount of the zinc salt in the presence of acatalytic amount of palladium leads to the formation of arylpyridineswith yields ranging from 84 to 99.5%, depending on the conditions, andalso to a substantial reduction in the amount of catalyst; in thisconnection, among other things, it was also observed that, in thepresence of a catalytic amount of the zinc salt, the palladium can beused in an amount of up to 1 mole for every 10,000 moles of arylpyridineproduct, which is undoubtedly surprising bearing in mind that, in thealready mentioned WO 97/40029, the catalyticity was approximately 0.6mole of nickel per 100 moles of bromopyridine. It is important toremember that the extremely high cost of palladium makes its use in anindustrial process economically disadvantageous if it is employed inmolar ratios with respect to the substrate of from 1:20 to 1:200.

In this connection, it should be noted that the use of catalytic amountsof zinc salts in combination with catalysts based on nickel or palladiumhad already been described by Miller and Farrell in Tetrahedron Letters,Vol. 39, 1998, 7275-8, and in the corresponding U.S. Pat. No. 5,922,898.However, those documents describe a method which permits the coupling ofGrignard compounds with aryl halides containing groups reactive towardsthe Grignard compounds, such as, for example, esters, ketones andnitrites, the presence of the zinc salt as a co-catalyst in this casemakes it possible to avoid the protection and deprotection of the groupsreactive towards the Grignard compounds. In the documents in question,the ratio of the catalyst (Pd or Ni) to the aryl halide is normallyapproximately 1:20 and, in any case, is never less than 1:100; thosedocuments also give examples demonstrating a high degree of inhibitionof the coupling reaction in the presence of a molar ratio of 1:1 betweenthe arylmagnesium reagent and ZnCl₂. The fairly high yields are alsopromoted by the presence of electron-attracting groups on the arylhalides, which increases the reactivity thereof in the aryl-arylcross-coupling reactions (V. V. Grushin, H. Alper Chem. Rev., 1994, 94,1047-1062).

In contrast, the subject-matter of the present invention is representedby a process for the preparation of arylpyridines in which anarylmagnesium halide is reacted with a halopyridine in the presence of acatalytic amount of a zinc salt and a catalytic amount of palladium,wherein the molar ratio of the palladium to the halopyridine is lessthan 1:100 and, normally, less than 1:1000.

In order to avoid any undesired secondary reactions, the arylmagnesiumhalide and the halopyridine should not contain other substituentscapable of interfering with the Grignard reaction or, if suchsubstituents are present, they should be in a suitably protected form;any carbonyl groups can be protected, for example, by being convertedbeforehand into the corresponding acetals.

According to its preferred embodiment, the process according to thepresent invention can thus he represented in the following scheme.

wherein: R₁, R₂ and R₃, which are the same or different from oneanother, represent H; a linear or branched C₁-C₆ alkyl; an aryl,preferably phenyl, optionally substituted by a linear or branched C₁-C₆alkyl; or, alternatively, R₁ and R₂ represent an optionally cyclicacetal group; and X₁ and X₂, which are the same or different from oneanother, represent Cl, Br or I.

In its more preferred embodiment, the process consists (a) in reactingan arylmagnesium halide of formula:

wherein X₁ represents Cl, Br or I; R₁ and R₂, which are the same ordifferent from one another, represent linear or branched C₁-C₆ alkyls,preferably methyls, or alternatively, R₁ and R₂ together represent asingle C₁-C₈ alkyl or alkylene group; R₃ represents hydrogen or a linearor branched C₁-C₆ alkyl or alkylene radical, with a halopyridine offormula:

wherein X₂ represents Cl, Br or I, in the presence of a catalytic amountof palladium and a catalytic amount of a zinc salt, relative to whichcompound 1 is prerferably used in dynamic deficiency, (and the molarratio of the palladium to the arylpyridine product being less than 1:100and, preferably, less than 1:1000); and (b) in transforming theintermediate compound so obtained into the desired compound byconverting the acetal group into a carbonyl group. In particular, it isrepresented by a process for the preparation of4-(2′-pyridyl)benzaldehyde in which: (a) an arylmagnesium halide offormula:

wherein X₁, R₁ and R₂ have the meaning given above, is reacted with ahalopyridine of formula:

wherein X₂ has the meaning given above, in the presence of a catalyticamount of palladium and a catalytic amount of a zinc salt, relative towhich compound 1 is used in dynamic deficiency (maintaining the molarratios of compounds 1bis to 2bis within the limits indicated above); and(b) the intermediate compound so obtained of formula:

is transformed into 4-(2′-pyridyl)benzaldehyde by converting the acetalgroup into a carbonyl group.

For the purposes of the present invention, the expression “catalyticamount” of the zinc salt means from 1 to 50 moles of zinc, preferablyfrom 5 to 35 moles, per 100 moles of halopyridine; the expression“catalytic amount” of palladium, however, means from 0.01 to 1 mole ofpalladium, preferably from 0.05 to 0.1 mole, per 100 moles ofhalopyridine; the expression “the Grignard compound is used in dynamicdeficiency relative to the zinc salt” means that the arylmagnesiumhalide is added dropwise to a solution already containing thehalopyridine, the palladium and the zinc salt. Finally, the term“catalyticity” means the molar ratio of the catalyst to thehalopyridine; owing to the fact that the process according to presentinvention results in an almost quantitative conversion of thehalopyridine into the arylpyridine product, the “catalyticity” inpractice coincides with the molar ratio of the catalyst to thearylpyridine product.

Both in its general version and in its preferred version or in its morepreferred version, the molar ratio of the palladium to the halopyridineis normally from 1:3000 to 1:1000, preferably approximately 1:2000; thehalopyridine is normally used in amounts of from 0.5 to 1.5 moles,preferably from 0.8 to 1.2 moles, per mole of arylmagnesium halide.

In order for the coupling reaction to take place with high yields and ahigh degree of selectivity in the presence of a minimum amount ofcatalyst, the Grignard reagent must be prevented from accumulating inthe reaction medium, and must thus be in dynamic deficiency relative tothe zinc salt; the amount of co-catalyst (Zn salts) necessary depends onthe regularity and the speed of addition of the Grignard compound: aratio of from 1:50 to 1:10 of the Zn salts to the halopyridine has beenfound to be satisfactory.

The zinc salt is generally selected from zinc chloride (ZnCl₂), zincbromide (ZnBr₂) and zinc acetate [Zn(OAc)₂]. However, the palladium isused principally in the form of palladium tetrakistriphenylphosphine[Pd(PPh₃)₄] or palladium salts, generally acetate or chloride, andphosphines. The phosphines which can be used for this purpose are wellknown in the art; it is preferable to use unsubstituted phosphines, suchas triphenylphosphine, or, alternatively, substituted phosphines, suchas tolyl phosphines. The ratio of the palladium to the phosphines isnormally one mole of palladium salt per 3-5 moles of phosphines. Thisreaction can also be carried out in the presence of bidentate ligands,such as, for example, bidentate phosphines, such as1,3-bis(diphenylphosphine)propane (dppp) or1,4-bis(diphenylphosphine)butane (dppb); the use of those ligands, incombination with palladium and the zinc salt, makes it possible toobtain molar yields higher than 97% (calculated on the halopyridine) anda catalyticity higher than 2000, using both bromopyridines and the moreeconomical and normally less reactive chloropyridines.

The coupling reaction is generally carried out at a temperature of25-85° C., preferably at 25-50° C., in an aprotic organic solvent thatdoes not react with a Grignard compound, preferably in tetrahydrofuranand/or toluene.

In the more preferred embodiment of the invention, the removal of theacetal group is effected by acid hydrolysis; that is to say, stage (b)is normally carried out by treating the intermediate (for example 3bis)with an acidic aqueous solution; this stage is preferably carried out byadding an aqueous HCl solution directly to the organic solution obtainedin stage (a) and by maintaining the temperature below 40° C.

It is also observed that, when the acetal group of compound 1 isobtained by reacting the corresponding carbonyl group with a C₁-C₈ diol(preferably with 1,3-propanediol, 1,2-butanediol, 1,4-butenediol or2,2-dimethyl-1,3-propanediol), the reaction proceeds without theoccurrence of secondary reactions or, at any rate, with the formation ofundesired secondary products being reduced to a minimum. A furthersubject of the present invention is therefore represented by a compoundof the general formula

and, preferably, by a compound of formula

wherein R represents precisely a linear or branched C₁-C₈ alkyl oralkenyl radical; the preferred radicals are: 1,3-propyl, 1,2-butyl,1,4-butenyl or 2,2-dimethyl-1,3-propyl.

Finally, as will be seen from the Examples, 4-(2′-pyridyl)benzaldehydecan be used for the preparation ofN-1-(tert-butoxycarbonyl)-N-2-[4-(2-pyridyl)-benzyl]-hydrazine andN-1-(tert-butoxycarbonyl)-N-2-{4-[(2-pyridyl)-phenyl]methyl-idene}-hydrazone,which are more advanced intermediates which can likewise be used in thesynthesis of the HIV protease inhibitors described above; furthersubjects of the invention are therefore represented by the proceduresfor the synthesis of these compounds which comprise a process for thepreparation of 4-(2′-pyridyl)benzaldehyde according to the presentinvention.

In conclusion, the process according to the present invention permitsthe synthesis of arylpyridines, and in particular of4-(2′-pyridyl)benzaldehydes, with particularly high, reproducible andindustrially satisfactory yields; with a high level of productivity,with a substantially lower use of palladium compared with that describedin the prior art for similar reactions, which is particularly importantfrom the point of view of the economical nature of the process, giventhe extremely high cost of palladium; without the presence ofelectron-attracting groups on the aryl halides. These and other aspectsof the invention will become clear from the following Examples which areto be regarded as non-limiting illustrations thereof.

EXAMPLES Example 1

Preparation of the Grignard reagent of 4-bromobenzaldehyde dimethylacetal

While regulating the temperature at from 30 to 35° C., iodine (0.2 g)and then, over a period of approximately one hour, a solution of4-bromobenzaldehyde dimethyl acetal (93 g, 0.394 mol) in tetrahydrofuran(80 g) are added to a suspension of magnesium (9.6 g, 0.394 mol) intetrahydrofuran (68 g) maintained at 30° C. with agitation under aninert atmosphere. The reaction mixture is maintained at 35° C. withagitation for one hour. Toluene (88 g) is added to the reaction mixture.

Coupling Reaction: Preparation of 4-(2′-pyridyl)benzaldehyde

Anhydrous zinc chloride (13.6 g 0.1 mol) and then 2-bromopyridine (52.8g, 0.334 mol) are added, with agitation under an inert atmosphere, to asolution constituted by toluene (156 g) and tetrahydrofuran (132 g).Palladium tetrakistriphenylphosphine (0.204 g, 0.178 mmol) and then,over a period of two hours, the Grignard solution are added to thesuspension maintained at 50° C. with agitation and under an inertatmosphere. The reaction mixture is maintained at 50° C. forapproximately 30 minutes and then cooled to 25° C.

A solution constituted by water (300 g) and 30% hydrochloric acid (70 g)is added to the reaction mixture over a period of approximately 30minutes. The mixture is maintained under agitation at 25° C.-30° C. forone hour and then the phases are separated. 30% ammonia is added to theaqueous phase up to a pH of 8, and then toluene (90 g) is added. Thephases are separated, the organic phase is evaporated under vacuum toyield a residue constituted by 4-(2′-pyridyl)benzaldehyde (61.1 g, 0.334mol; yield in moles relative to the 2-bromopyridine added: 100%;turnover of the catalyst (Pd) 1876).

IR: 1695.7 cm⁻¹ (aldehyde C═O stretching); M.P.: 52°-53° C.; ¹H-NMR (300MHz, CDCl₃): ppm 10.2 (1H, s); 8.8 (1H,dt, J=4.8 Hz, J=1.4 Hz); 8.25(2H, part B of an AB system, J=7.0 Hz); 8.15 (2H, part A of an ABsystem, J=7.0 Hz); 7.8 (2H, AB system, J=8.6 Hz, J=1.4 Hz); 7.35 (1H,m).

The product as identified by comparison with an authentic sampleprepared in accordance with Example 37b described in patent WO97/40029.

Comparative Example 2

Preparation of 4-(2′-pyridyl)benzaldehyde

Example 1 was repeated without the addition of the catalytic amount ofzinc chloride. The yield in moles of 4-(2′-pyridyl)benzaldehyde relativeto the 2-bromopyridine added was 1%, the turnover of the catalyst (Pd)18.

Example 3

Preparation of 4-(2′-pyridyl)benzaldehyde

Example 1 was repeated using palladium acetate (0.040 g, 0.178 mmol) andtriphenylphosphine (0.186 g, 0.712 mmol) instead of palladiumtetrakistriphenylphosphine. The yield in moles of4-(2′-pyridyl)benzaldehyde relative to the 2-bromopyridine added was 91%the turnover of the catalyst (Pd) 1707.

Example 4

Preparation of 4-(2′-pyridyl)benzaldehyde

Example 1 was repeated using palladium acetate (0.04 g, 0.178 mmol) andtriphenylphosphine (0.186 g, 0.712 mmol) instead of palladiumtetrakistriphenylphosphine and a different amount of anhydrous zincchloride (18.2 g, 0.133 mol). The yield in moles of4-(2′-pyridyl)benzaldehyde relative to the 2-bromopyridine added was88%, the turnover of the catalyst (Pd) 1650.

Example 5

Preparation of 4-(2′-pyridyl)benzaldehyde

Example 1 was repeated using a different amount of zinc chloride (2.28g, 0.0167 mol). The yield in moles of 4-(2′-pyridyl)benzaldehyderelative to the 2-bromopyridine added was 93%, the turnover of thecatalyst (Pd) 1744.

Example 6

Preparation of 4-(2′-pyridyl)benzaldehyde

Example 1 was repeated using anhydrous zinc bromide (22.5 g, 0.10 mol)instead of zinc chloride. The yield in moles of4-(2′-pyridyl)benzaldehyde relative to the 2-bromopyridine added was93%, the turnover of the catalyst (Pd) 1744.

Example 7

Preparation of 2-(4′-bromophenyl)-5,5-dimethyl-1,3-dioxane

A mixture constituted by 4-bromobenzaldehyde (100 g, 0.54 mol), toluene(300 ml), monohydrated p-toluenesulphonic acid (2.79 g, 0.0162 mol) and2.2-dimethyl-1,3-propanediol (84 g, 0.81 mol) is maintained underagitation at 125° C. for 4 hours while the water is removed byazeotropic distillation using a Florentine flask.

A 30% solution of sodium methoxide in methanol (5.8 g, 0.0324 mol) isadded to the reaction mixture cooled to 30° C. The whole is cooled to25° C. and washed with water (2×100 ml). The phases are separated andthe organic phase is reduced to a residue. Heptane (137 ml) is added tothe dry residue and the whole is heated at 40° C. until dissolution iscomplete. The whole is cooled to 10° C. to give a suspension. Afterfiltration and evaporation of the solvent under vacuum, a residue isobtained which is constituted by2-(4′-bromophenyl)-5,5-dimethyl-1,3-dioxane (91 g, 0.335 mol, 62%).

¹H-NMR (300 MHz, CDCl₃), ppm 0.8 (3H, s); 1.3 (3H, s); 3.65 (2H, part Aof an AB system, J=10.6 Hz); 3.8 (2H, part B of an AB system, J=10.6Hz); 5.4 (1H, s); 7.4 (2H, part A of an AB system, J=8.4 Hz); 7.5 (2H,part B of an AB system, J=8.4 Hz).

Preparation of the Grignard Reagent of2-(4′-bromophenyl)-5,5dimethyl-1,3-dioxane

While regulating the temperature at from 30 to 35° C., iodine (0.05 g)and then, over a period of approximately one hour, a solution of2-(4′-bromophenyl)-5.5-dimethyl-1,3-dioxane (26.7 g, 0.098 mol) intetrahydrofuran (20 g) are added to a suspension of magnesium (2.4 g,0.0985 mol) in tetrahydrofuran (17 g) maintained at 30° C. withagitation under an inert atmosphere. The reaction mixture is maintainedat 35° C. with agitation for one hour. Toluene (22 g) is added to thereaction mixture.

Coupling Reaction: Preparation of 4-(2′-pyridyl)benzaldehyde

Anhydrous zinc chloride (3.4 g, 0.025 mol) and then 2-bromopyridine(13.2 g, 0.0835 mol) are added, with agitation under an inertatmosphere, to a solution constituted by toluene (39 g) andtetrahydrofuran (33 g).

Palladium tetrakistriphenylphosphine (0.051 g, 0.0442 mmol) and then,over a period of approximately 2 hours, the Grignard solution are addedto the suspension maintained at 50° C. with agitation and under an inertatmosphere. The reaction mixture is maintained at 50° C. forapproximately 30 minutes and then cooled to 25° C.2-[4′-(2-pyridyl)phenyl]-5,5-dimethyl-1,3-dioxane is obtained with ayield of 84% in moles relative to the 2-bromopyridine added. Acidhydrolysis results in the formation of 4-(2′-pyridyl)benzaldehyde withan almost quantitative yield, turnover of the catalyst (Pd) 1889.

Comparative Example 8

Preparation of 4-(2′-pyridyl)benzaldehyde

Example 7 was repeated without the addition of the catalytic amount ofzinc chloride. The yield in moles of 4-(2′-pyridyl)benzaldehyde relativeto the 2-bromopyridine added was 2%, turnover of the catalyst (Pd) 37.

Example 9

Preparation of the Grignard Reagent of 4-bromobenzaldehyde dimethylacetal

A chip of iodine (50 mg) and p-bromobenzaldehyde dimethyl acetal (6.8 g,98%, 0.029 mol) are added to a suspension of magnesium filings (7.0 g,0.287 mol) in tetrahydrofuran (109 g) maintained at 30° C. withagitation under an inert atmosphere: after a few minutes, the reactionis triggered and the internal temperature reaches 35° C. At the end ofthe exothermic reaction, a solution of p-bromobenzaldehyde dimethylacetal (62.4 g, 98%, 0.262 mol) in tetrahydrofuran (64.3 g) is addedover a period of 1.5 hours while regulating the temperature at from 30to 35° C. The reaction mixture is maintained under agitation at 30° C.for one hour.

Coupling Reaction: Preparation of 4-(2′-pyridyl)benzaldehyde

2-bromopyridine (38.92 g, 0.246 mol) and palladiumtetrakistriphenylphosphine (0.135 g, 0.117 mmol) are added to a mixtureof ZnCl₂ (3.08 g, 0.0226 mol) in tetrahydrofuran (59.6 g) maintained at50° C. with agitation under an inert atmosphere. The Grignard solution(249.5 g of solution, equal to 0.291 mol) is added dropwise over a totalof 3 hours to the resulting suspension, which is still maintained at 50°C. with agitation under an inert atmosphere. The reaction mixture ismaintained at 50° C. for 30 minutes and then cooled to 18° C.

A solution constituted by water (126 g) and 30% hydrochloric acid (40 g)is added to the reaction mixture, keeping the temperature of the mixturebelow 35° C. After 30 minutes' agitation at 25° C., toluene (44 g) isadded and the phases are separated. Toluene (87 g) and 30% ammonia (42g) are added to the aqueous phase, and the phases are separated toyield, as the organic phase, a solution of 4-(2′-pyridyl)benzaldehyde(210.8 g, HPLC strength 20.6%, equal to 43.42 g, 0.237 mol; yield inmoles relative to the 2-bromopyridine added: 96.4%, turnover of catalyst(Pd): 2028).

Example 10

Preparation of 4-(2′-pyridyl)benzaldehyde

Example 9 is repeated using a different amount of ZnCl₂ (0.1 g, 0.73mmol), to give a molar yield of 4-(2′-pyridyl)benzaldehyde relative tothe 2-bromopyridine added of 81.2%, turnover of the catalyst (Pd) equalto 1700.

Comparative Example 11

Preparation of 4-(2′-pyridyl)benzaldehyde

A solution of the Grignard reagent of 4-bromobenzaldehyde dimethylacetal (51.4 g of solution, equal to 0.060 mol), prepared analogously toExample 9, is added dropwise over a total of 3 hours to a solution of2-bromopyridine (8.04 g, 0.0509 mol) and palladiumtetrakistriphenylphosphine (0.29 g, 0.25 mmol) in tetrahydrofuran (24 g)maintained at 50° C. with agitation under an inert atmosphere. Thereaction mixture is maintained at 50° C. for one hour and then cooled to25° C.

A yield of 4-(2-pyridyl)benzaldehyde solution of 3.8% relative to the2-bromopyridine added is obtained, turnover of the catalyst (Pd) 76.

Example 12

Preparation of 4-(2′-pyridyl)benzaldehyde

2-bromopyridine (8.07 g, 0.051 mol) and palladiumtetrakistriphenylphosphine (0.032 g, 0.028 mmol) and then, over a totalof 3 hours, a solution of the Grignard reagent of 4-bromobenzaldehydedimethyl acetal (50 g of solution, equal to 0.058 mol), preparedanalogously to Example 9, are added to a mixture of ZnCl₂ (7.12 g, 0.052mol) in tetrahydrofuran (24.2 g) maintained at 50° C. with agitationunder an inert atmosphere. The reaction mixture is maintained at 50° C.for 30 minutes and then cooled to 25° C.

A solution constituted by water (30 g) and 30% hydrochloric acid (9 g)is added to the reaction mixture and the mixture is maintained underagitation for 2 hours at 25° C. A portion of the solvent (30 g) isevaporated under vacuum and replaced by an equal amount of toluene andthen the phases are separated. Toluene (30 g) and 30% ammonia (14 g) areadded to the aqueous phase. The phases are separated to give a solutionof 4-(2′-pyridyl)benzaldehyde (53.74 g, HPLC strength 16.66%, equal to8.95 g, 0.0489 mol; yield in moles relative to the 2-bromopyridineadded: 96%; turnover of the catalyst (Pd): 1920).

Example 13

Preparation of 4-(2′-pyridyl)benzaldehyde

A solution of the Grignard reagent of 4-bromobenzaldehyde dimethylacetal (63 g of solution, containing 0.074 mol), prepared analogously toExample 9, is added dropwise over a total of 6 hours to a solution of2-bromopyridine (7.95 g, 0.050 mol), ZnCl₂ (0.0071 g, 0.052 mmol) andpalladium tetrakistriphenylphosphine (0.032 g, 0.028 mmol) intetrahydrofuran (23.6 g) maintained at 50° C. with agitation under aninert atmosphere. The reaction mixture is maintained at 50° C. for 30minutes and then cooled to 25° C.

A solution constituted by water (28 g) and 30% hydrochloric acid (9 g)is added to the reaction mixture and the mixture is maintained underagitation for 2 hours at 25° C. 30 g of solvent are evaporated undervacuum and replaced by an equal amount of toluene and then the phasesare separated. Toluene (30 g) and 30% ammonia (12 g) are added to theaqueous phase. After filtering over a panel of Celite the solid at theinterphase and washing the panel with toluene, the phases are separatedto give a solution of 4-(2′-pyridyl)benzaldehyde (73.53 g, HPLC strength11.1%, equal to 8.16 g, 0.0446 mol; yield in moles relative to the2-bromopyridine added 89%; turnover of catalyst (Pd): 1620; turnover ofZn: 890).

Example 14

Preparation of 4-(2′-pyridyl)benzaldehyde

2-bromopyridine (7.90 g, 0.050 mol) and palladiumtetrakistriphenylphosphine (0.029 g, 0.025 mmol) and then, at atemperature of 70° C. and over a total of 3 hours, a solution of theGrignard reagent of 4-bromobenzaldehyde dimethyl acetal (53 g ofsolution, containing 0.062 mol), prepared analogously to Example 9, areadded to a mixture of ZnCl₂ (0.72 g, 0.0053 mol) in tetrahydrofuran(12.4 g) maintained under agitation under an inert atmosphere. Thereaction mixture is maintained at 70° C. for 30 minutes and then cooledto 25° C.

A solution constituted by water (28 g) and 30% hydrochloric acid (10 g)is added to the reaction mixture and the mixture is maintained underagitation for 2 hours at 25° C. Toluene (30 g) and 30% ammonia (9.7 g),are added and the phases are separated to give a solution of4-(2′-pyridyl)benzaldehyde (53.5 g, HPLC strength 17%, equal to 9.09 g,0.049 mol; yield in moles relative to the 2-bromopyridine added: 99%,turnover of catalyst (Pd): 1960).

Example 15

Preparation of Grignard Reagent

While regulating the temperature at from 30° to 35° C., iodine (0.05 g)and then, over a period of approximately 1 hour, a solution ofpara-bromotoluene (16.9 g, 0.0985 mol) in tetrahydrofuran (20 g) areadded to a suspension of magnesium (2.4 g, 0.0985 mol) intetrahydrofuran (17 g) maintained at 30° C. with agitation under aninert atmosphere. The reaction mixture is maintained at 35° C. withagitation for 1 hour. Toluene (22 g) is added to the reaction mixture.

Coupling Reaction: Preparation of 4-(2′-pyridyl)toluene

Anhydrous zinc chloride (3.4 g, 0.025 mol) and then 2-bromopyridine(13.2 g, 0.0835 mol) are added, with agitation under an inertatmosphere, to a solution constituted by toluene (39 g) andtetrahydrofuran (33 g).

Palladium tetrakistriphenylphosphine (0.051 g, 0.0442 mmol) and then,over a period of 2 hours, the Grignard solution are added to thesuspension maintained at 50° C. with agitation and under an inertatmosphere.

The reaction mixture is maintained at 50° C. for 30 minutes and thencooled to 25° C.

A solution constituted by water (75 g) and 30% hydrochloric acid (17.5g) is added to the reaction mixture over a period of 30 minutes. Themixture is maintained under agitation at 25-30° C. for 1 hour and thenthe phases are separated.

30% ammonia is added to the aqueous phase up to a pH of 8, followed bytoluene (45 g).

The phases are separated and the organic phase is evaporated undervacuum to give a residue constituted by 4-(2′-pyridyl)toluene (13.7 g,0.08 mol—yield in moles relative to the 2-bromopyridine added: 97.1%,turnover of the catalyst (Pd): 1834).

¹H-NMR (300 MHz, CDCl₃): ppm 2.4 (3H, s); 7.2 (1H, m); 7.3 (2H, d, J=8.0Hz); 7.75 (2H, part B of an AB system, J=6.0 Hz); 7.9 (2H, part A of anAB system, J=6.0 Hz); 8.7 (1H, dt, J=1.4 Hz, J=3.2 Hz).

The product was identified by comparison with an authentic ALDRICHsample (ALDRICH catalogue 1999-2000, page 1679, cod. 46.539-9).

Comparative Example 16

Preparation of 4-(2′-pyridyl)toluene

Example 15 was repeated but without using zinc chloride. The yield inmoles of 4-(2-pyridyl)toluene relative to the 2-bromopyridine added was9%, the turnover of the catalyst (Pd) is 170.

Example 17

Preparation of 4-(2′-pyridyl)benzaldehyde

Anhydrous zinc chloride (13.6 g, 0.10 mol) and then 2-chloropyridine(39.9 g, 0.29 mol) are added, with agitation under an inert atmosphere,to a solution constituted by toluene (156 g) and tetrahydrofuran (12 g).

Palladium tetrakistriphenylphosphine (1.77 g, 0.00153 mol) and then,over a period of 2 hours at 85° C., a solution of the Grignard reagentof 4-bromobenzaldehyde dimethyl acetal (338.6 g of solution, equal to0.394 mol), prepared analogously to Example 1, are added to thesuspension maintained at 50° C. with agitation and under an inertatmosphere. The reaction mixture is maintained at 85° C. forapproximately 30 minutes and then cooled to 25° C. A solutionconstituted by water (300 g) and 30% hydrochloric acid (70 g) is addedto the reaction mixture over a period of approximately 30 minutes. Themixture is maintained under agitation at 25° C.-30° C. for one hour andthe phases are separated. 30% ammonia (32 g) is added to the underlyingaqueous phase up to a pH of 8, followed by toluene (90 g).

The phases are separated and the organic phase is evaporated undervacuum to give a residue constituted by 4-(2′-pyridyl)benzaldehyde (44.6g, 0.243 mol, yield in moles relative to the 2-chloropyridine added: 84%, turnover of the catalyst (Pd) 160).

Example 18

Preparation of 4-(2′-pyridyl)benzaldehyde

2-chloropyridine (27.95 g, 0.246 mol), palladium acetate (0.0276 g,0.123 mmol) and 1,3-bis(diphenylphosphine)propane (0.0509 g, 0.123 mmol)are added to a mixture of ZnCl₂ (1.8 g, 0.013 mol) in tetrahydrofuran(53.3 g) maintained at 50° C. with agitation under an inert atmosphere.A solution of the Grignard reagent of 4-bromobenzaldehyde dimethylacetal (239.6 2 of solution, containing 0.279 mol), prepared analogouslyto Example 9, is added dropwise over a total of 3 hours to the resultingsuspension, still at 50° C. and under agitation under an inertatmosphere. The reaction mixture is maintained at 50° C. for 30 minutesand then cooled to 18° C.

A solution constituted by water (126 g) and 30% hydrochloric acid (40 g)is added to the reaction mixture, keeping the temperature of the mixturebelow 35° C. After agitation for 1 hour at 25° C., toluene (44 g) isadded and the phases are separated. Toluene (87 g) and 30% ammonia (42g) are added to the aqueous phase and the phases are separated to give,as the organic phase, a solution of 4-(2′-pyridyl)benzaldehyde (197.1 g,HPLC strength 22.2%, equal to 43.75 g, 0.239 mol; yield in molesrelative to the 2-chloropyridine added: 97%, turnover of the catalyst(Pd): 1940).

Example 19

Preparation of 4-(2′-pyridyl)benzaldehyde

Example 18 is repeated using a different amount of ZnCl₂ (1.0 g, 0.0073mol), to give a molar yield relative to the 2-chloropyridine added of97.8%, turnover of the catalyst (Pd) equal to 1974.

Example 20

Preparation of 4-(2′-pyridyl)benzaldehyde

Example 18 is repeated using a different amount of THF (114 g) in thecoupling reaction and adding the Grignard reagent at 70° C. (instead ofat 50° C.): a molar yield relative to the 2-chloropyridine added of99.4% is obtained, turnover of catalyst (Pd) equal to 2075.

Example 21

Preparation of 4-(2′-pyridyl)benzaldehyde

A solution of the Grignard reagent of 4-bromobenzaldehyde dimethylacetal (49.2 g of solution, corresponding to 0.057 mol), preparedanalogously to Example 9, is added dropwise over a total of 3 hours to amixture of 2-chloropyridine (5.82 g, 0.051 mol), ZnCl₂ (0.48 g, 0.00352mol), palladium acetate (0.00582 g, 0.026 mmol),1,4-bis(diphenylphosphine)butane (0.0115 g, 0.027 mmol) intetrahydrofuran (26.2 g) maintained at 70° C. with agitation under aninert atmosphere. The reaction mixture is maintained at 70° C. for 30minutes and then cooled to 25° C.

A quantitative yield of 4-(2′-pyridyl)benzaldehyde is obtained relativeto the chloropyridine added, turnover of the catalyst (Pd) of 1969.

Comparative Example 22

Preparation of 4-(2′-pyridyl)benzaldehyde

Example 21 was repeated in the absence of zinc chloride. A yield inmoles of 4-(2′-pyridyl)benzaldehyde of 26% was obtained relative to the2-chloropyridine added, palladium turnover of 520.

Example 23

Preparation of 4-(2′-pyridyl)benzaldehyde

2-chloropyridine (7.17 g, 0.063 mol), palladium acetate (0.0070 g, 0.031mmol) and 1,3-bis(diphenylphosphine)propane (0.013 g, 0.033 mmol) areadded to a mixture of ZnCl₂ (0.42 g, 3.08 mmol) in tetrahydrofuran (13.7g) maintained at 30° C. with agitation under an inert atmosphere. Asolution of the Grignard reagent of 4-bromobenzaldehyde dimethyl acetal(80.5 g of solution, containing 0.070 mol), prepared analogously toExample 9, is added dropwise over a total of 3.5 hours to the resultingsuspension, still at 30° C. and under agitation under an inertatmosphere. The reaction mixture is maintained at 30° C. for 30 minutesand then cooled to 18° C.

A solution constituted by water (32 g) and 30% hydrochloric acid (10.3g) is added to the reaction mixture, keeping the temperature of themixture below 35° C. After 1 hour's agitation at 25° C., toluene (11 g)is added and the phases are separated. Toluene (22 g) and 30% ammonia(11 g) are added to the aqueous phase and the phases are separated togive, as the organic phase, a solution of 4-(2′-pyridyl)benzaldehyde(48.6 g, HPLC strength 22.7%, equal to 11.0 g, 0.060 mol; yield in molesrelative to the 2-chloropyridine added: 95%, turnover of the catalyst(Pd): 1941).

Example 24

Preparation of 4-(3′-pyridyl)benzaldehyde

Anhydrous zinc chloride (6.8 g, 0.05.0 moles) and then 3-bromopyridine(26.4 g, 0.167 mol) are added with agitation under an inert atmosphere,to a solution constituted by toluene (78 g) and tetrahydrofuran (66 g).

Palladium tetrakistriphenylphosphine (0.102 g, 0.089 mmol) and then,over a period of 2 hours, a solution of the Grignard reagent of4-bromobenzaldehyde dimethyl acetal (169.3 g of solution, equal to 0.197mol), prepared analogously to Example 1, are added to the suspensionmaintained at 50° C. with agitation and under an inert atmosphere.

The reaction mixture is maintained at 50° C. for 30 minutes and thencooled to 25° C.

4-(3′-pyridyl)benzaldehyde (25.6 g, 0.14 mol) is obtained with a yieldof 84% in moles relative to the 3-bromopyridine added, turnover of thecatalyst (Pd): 1576.

IR: 1701.6 cm⁻¹ (aldehyde C—O stretching)

m.p.: 52°-53° C.

¹H-NMR (300 MHz, CDCl₃): ppm 10.1 (1H, s); 8.9 (1H, d, J=2.2 Hz); 8.7(1H, dd, J=1.6 Hz, J=4.9 Hz); 8.02 (2H, part A of an AB system, J=8.2Hz); 7.97 (1H, ddd, J=2.2 Hz, J=7.9 Hz, J=1.6 Hz); 7.78 (2H, part B ofan AB system, J=8.2 Hz); 7.45 (1H, dd, J=4.9 Hz, J=7.9 Hz)

Comparative Example 25

Preparation of 4-(3′-pyridyl)benzaldehyde

Example 24 was repeated but in the absence of zinc chloride. The yieldin moles of 4-(3′-pyridyl)benzaldehyde relative to the 3-bromopyridineadded was 3%, turnover of the catalyst (Pd) 56.

Example 26

Preparation of 4-(4′-pyridyl)benzaldehyde

Anhydrous zinc chloride (6.8 g, 0.050 moles) and then 4-bromopyridine(26.4 g, 0.16 mol) are added, with agitation under an inert atmosphere,to a solution constituted by toluene (78 g) and tetrahydrofuran (66 g).

Palladium tetrakistriphenylphosphine (0.102 g, 0.089 mmol) and then,over a period of 2 hours, a solution of the Grignard reagent of4-bromobenzaldehyde dimethyl acetal (169.3 g of solution, equal to 0.197mol) prepared analogously to Example 1, are added to the suspensionmaintained at 50° C. with agitation and under an inert atmosphere.

The reaction mixture is maintained at 50° C. for 30 minutes and thencooled to 25° C.

4-(4′-pyridyl)benzaldehyde (27.5 g, 0.15 mol) is obtained with a yieldof 90% in moles relative to the 4-bromopyridine added, turnover of thecatalyst (Pd): 1685.

Example 27

Preparation ofN-1-(tert-butoxycarbonyl)-N-2-{4-[(2-pyridyl)-phenyl]-methylidene}-hydrazone

A solution of 2 g (1.05 mmol) of 4-(2′-pyridyl)-benzaldehyde and 1.37 g(1 mmol) of tert-butyl carbazate in 30 ml of ethanol is agitated at 80°C. for 5 hours (after 4 hours a further 0.05 equivalent of tert-butylcarbazate is added). The reaction mixture is cooled and diluted withwater; the product separates from the mixture in the form of crystals.

TLC: Rf=0.51 (methylene chloride:methanol=15:1) ¹H-NMR (200 MHz, CDCl₃):ppm 8.68 (1H, m); 8.21 (1H, s); 7.98 (2H, portion A of an AB system, J=9Hz); 7.85 (1H, s); 7.8-7.6 (4H, m); 7.22 (1H, m); 1.53 (9H, s).

Example 28

Preparation ofN-1-(tert-butoxycarbonyl)-N-2-[4-(2′-pyridyl)-benzyl]-hydrazine

2 g (6.7 mmol) ofN-1-(tert-butoxycarbonyl)-N-2-{4-[(2-pyridyl)-phenyl]-methylidene}-hydrazoneand 0.2 g of palladium/C 5% in 30 ml of methanol, are hydrogenated atambient pressure and at ambient temperature for 8 hours. The catalyst isfiltered and washed with methanol. The solvent is removed bydistillation at reduced pressure. An oily residue is obtained which, bycrystallisation from cyclohexane, provides a colourless solid having am.p. of 77-79° C.

TLC: Rf=0.46 (methylene chloride:methanol=15:1) ¹H-NMR (200 MHz, CDCl₃):ppm 8.69 (1H, m); 7.69 (2H, d, J=2 Hz); 7.45 (2H, d, J=2 Hz); 7.8-7.65(2H, m); 7.22 (1H, m); 4.06 (2H,s); 1.47 (9H, s).

What is claimed is:
 1. A process for the preparation of4-(2′-pyridyl)benzaldehyde comprising: reacting an arlymagnesium halideof the formula

 wherein X₁ represents Cl, Br or I; R₁ and R₂ which are the same ordifferent from one another, represent linear or branched C₁-C₆ alkylsor, alternatively, R₁ and R₂ together represent a single linear orbranched C₁-C₆ alkylene group, with a halopyridine of formula

 wherein X₂ represents Cl, Br, or I, in the presence of a catalyticamount of Zinc salt and a catalytic amount of Palladium, the molar ratioof the palladium to the halopyridine of formula 2 being less than1:1000, to create an intermediate compound; and (b) converting theacetal group into a carbonyl group by acidic hydrolysis.
 2. A processaccording to claim 1, characterized in that the arylmagnesium halide offormula 1 is used in dynamic deficiency relative to the zinc salt.
 3. Aprocess according to claim 1, characterized in that the halopyridine offormula 2 is 2-chloropyridine.
 4. A process according to claim 1,characterized in that the arylmagnesium halide of formula 1 is a bromideor a chloride.
 5. A process according to claim 1, characterized in thatthe zinc salt is selected from ZnCl₂, ZnBr₂ and/or Zn(OAc)₂.
 6. Aprocess according to claim 1, characterized in that the zinc salt ispresent in an amount of 1-50 moles per 100 moles of halopyridine.
 7. Aprocess according to claim 1, characterized in that the palladium isused in the form of Pd(PPh₃)₄ and/or Pd(OAc)₂+4 PPh₃.
 8. A processaccording to claim 1, characterized in that the palladium is used in anamount of 0.01-1 mole per 100 moles of halopyridine.
 9. A processaccording to claim 1, characterized in that the halopyridine of formula2 is used in an amount of 0.8-1.2 moles, per mole of arylmagnesiumhalide of formula
 1. 10. A process according to claim 1, characterizedin that it is carried out in the presence of bidentate ligands.
 11. Aprocess according to claim 10, characterized in that the bidentateligands are bidentate phosphines.
 12. A process according to claim 11,characterized in that the bidentate phosphines are selected from1,3-bis(diphenylphosphine)propane, 1,4-bis(diphenylphosphine)butane, and1,1′-diphenylphosphineferrocene.
 13. A process according to claim 11,characterized in that the bidentate phosphines are used in an equimolarratio with the palladium.
 14. A process according to claim 1,characterized in that stage (a) is carried out at a temperature of 0-85°C.
 15. A process according to claim 1, characterized in that stage (a)is carried out in an aprotic organic solvent.
 16. A process according toclaim 1, characterized in that stage (b) is carried out by acidhydrolysis.
 17. A process according to claim 16, characterized in thatthe acid hydrolysis is carried out at temperatures lower than 40° C. 18.A process according to claim 1, characterized in that R₁ and R₂ are bothmethyls.
 19. A process according to claim 1, characterized in that R₁and R₂, together, are selected from 1,3-propyl, 1,2-butyl, 1,4-butenyland 2,2-dimethyl-1,3-propyl.
 20. A process according to claim 1,characterized in that the molar ratio of the palladium to thehalopyridine of formula 2 is from 1:3000 to 1:1000.
 21. A processaccording to claim 6, characterzed in that the zinc salt is present inan amount of 5-30 moles per 100 moles of halopyridine.
 22. A processaccording to claim 8, characterized in that the palladium is used in anamount of 0.05-0.1 mole per 100 moles of halopyridine.
 23. A processaccording to claim 14, characterized in that stage (a) is carried out ata temperature of 30-50° C.
 24. A process according to claim 15,characterized in that stage (a) is carried out in tetrahydrofuran and/ortoluene.